Leukemia Specialists Review the Role of FLT3 Inhibitors Across AML Treatment Settings

The Role of FLT3 Inhibitors Across AML Treatment Settings

For the Oncology Brothers podcast Clinical Insights series, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with leukemia experts Uma Borate, MBBS, of The Ohio State University, and Naval Daver, MD, and Nicholas Short, MD, of The University of Texas MD Anderson Cancer Center (UT MD Anderson). The doctors discussed FLT3-mutated AML and the role of FLT3 inhibitors across induction, consolidation, maintenance, and salvage settings. 

FLT3-Mutated AML: Testing and Subtypes

Roughly 20% to 30% of patients under 60 with AML will have a FLT3 mutation, categorized as either an internal tandem duplication (ITD) or a tyrosine kinase domain (TKD). ITD mutations make up about 80% of the FLT3-mutated population and are associated with a poorer prognosis compared with TKD. 

Historically, any FLT3 mutation was considered an adverse risk marker. However, prognosis has improved over time due to greater understanding of molecular profiles, better detection, earlier intervention, and the development of FLT3 inhibitors and other novel treatments, including HMAs plus venetoclax. Emerging data even suggest that some subgroups, such as those with FLT3-ITD and NPM1 comutation, can forgo hematopoietic cell transplantation (HCT) if they achieve deep minimal residual disease (MRD) negativity, which is a true paradigm shift, Dr. Short said. 

Given the development of targeted therapies for FLT3 and other AML subtypes, oncologists should perform next-generation sequencing (NGS) testing immediately at diagnosis to determine if these agents can be incorporated into induction therapy. Testing should be repeated during treatment and especially at relapse, as several mutations including FLT3 can be acquired or lost in a significant number of patients. Targeted therapies are particularly valuable next-line options for patients with AML who acquire targetable alterations, Dr. Daver said. 

Frontline and Salvage Therapy With FLT3 Inhibitors 

Four FLT3 inhibitors are commonly used in FLT3–mutated AML: first-generation agents midostaurin and sorafenib and second-generation agents quizartinib and gilteritinib. Midostaurin and gilteritinib are classified as type I FLT3 inhibitors, whereas sorafenib and quizartinib are type II inhibitors. Both types are effective for FLT3-ITD mutations, but only type I is also effective for FLT3-TKD mutations. Compared with the first-generation inhibitors, quizartinib and gilteritinib have shown greater potency and better tolerability, and they are preferred options in different treatment settings.

In the frontline setting, FLT3 inhibitors are typically combined with an induction backbone, whether with 7 + 3 chemotherapy or HMA plus venetoclax. Quizartinib is the predominant choice in this setting based on positive survival data from the QuANTUM-First trial. In the relapsed or refractory FLT3-mutated AML setting, the ADMIRAL trial established gilteritinib monotherapy as standard of care, although trials are evaluating novel FLT3 inhibitor combinations. Even with novel combinations, the goal for patients with relapsed or refractory FLT3-mutated AML should be to bridge to HCT whenever possible, Dr. Short said. 

Postconsolidation and Post-HCT Maintenance Strategies

Some available data support FLT3 inhibitor maintenance strategies in both postconsolidation therapy and post-HCT settings. In the postconsolidation space, follow-up data from QuANTUM-First showed quizartinib maintenance provided a significant benefit in patients with FLT3-ITD–AML who did not go on to HCT after completing induction and consolidation. Based on these data, the FDA approved quizartinib for postconsolidation maintenance. When using this approach, patients should be monitored for MRD with FLT3-specific NGS every 3 months to confirm the presence of FLT3 mutations, Dr. Daver said. 

In the post-HCT setting, phase 3 MORPHO trial data support FLT3 inhibitor maintenance. Although the primary analysis for relapse-free survival (RFS) just missed statistical significance (HR, 0.679; 95% CI, 0.495-1.005; P = .0518), gilteritinib did improve RFS for the subgroup of patients with FLT3-ITD AML with detectable MRD before or after HCT (HR, 0.515; 95% CI, 0.316-0.838; P = .0065). Dr. Daver’s center uses this strategy in posttransplant patients, although the optimal duration for treatment is unclear. Currently, the center employs 2 years of therapy with routine MRD monitoring every 3 months, potentially discontinuing FLT3 inhibitor maintenance if a patient achieves MRD negativity. 

Emerging FLT3 Inhibitor Combinations

The development of HMA plus venetoclax was a significant advance for AML, but these regimens are not as effective in the frontline setting for FLT3-ITD–mutated AML. Preclinical data showed FLT3 inhibitors had synergy with HMA and venetoclax, and trials in the salvage setting supported increased efficacy with gilteritinib, HMA, and venetoclax triplet therapy. The subsequent phase 1/2 VICEROY study evaluated gilteritinib, venetoclax, and azacitidine in the frontline setting and showed the triplet improved complete response and overall survival rates versus historical HMA plus venetoclax outcomes. Notably, these triplet regimens require reduced dosing schedules of both venetoclax and the FLT3 inhibitor to improve tolerability. 

A randomized phase 3 trial for FLT3 inhibitor triplets may be unlikely given the successful phase 1/2 data, Dr. Daver said. He urged oncologists to refer these patients to clinical trials to generate enough data to support the addition of FLT3 inhibitor, HMA, and venetoclax triplets to guideline recommendations for frontline treatment of FLT3-mutated AML. In the future, these triplets may also be used to bridge relapsed or refractory patients to HCT, although more data are needed.

Managing Adverse Effects of FLT3 Inhibitors

FLT3 inhibitors as a class are associated with cytopenias and related infection risk, QTc interval prolongation, liver function test abnormalities, and pericardial and pleural effusion. However, adverse effect profiles differ between FLT3 inhibitors. Midostaurin has broader inhibition and is associated with more off-target adverse effects, including gastrointestinal events. Quizartinib is more commonly associated with QTc interval prolongation and requires careful selection of non-QTc–affecting prophylaxis. Gilteritinib is linked to lower rates of QTc prolongation, but differentiation syndrome has been reported, more often with gilteritinib monotherapy than with combinations. 

Historically, growth factor support for cytopenias was avoided in patients with leukemia. Over time, data has supported the safety of growth factors for patients without marrow involvement. In Dr. Borate’s practice, she aggressively uses growth factor support for patients with prolonged cytopenias provided bone marrow biopsies do not show an increase in blasts. Growth factor support alleviates cytopenias and reduces infection risk, allowing for longer treatment, Dr. Borate said. 

Community Perspective

Community practices can partner with tertiary or quaternary centers to offer FLT3 inhibitor therapy for patients with FLT3-mutated AML. At UT MD Anderson, Drs. Daver and Short’s team often admits patients for the first cycle of frontline induction therapy with FLT3 inhibitor combinations. Typically, patients continue treatment in the community setting with guidance from the referral center, which they occasionally visit for monitoring. Generally speaking, community oncologists should be cautious when using combinations in any setting and review any treatment changes with partners to ensure no dosing issues occur, the doctors suggested.